Growth Hormone and Insulin Signaling in Acromegaly: Impact of Surgery Versus Somatostatin Analog Treatment

Abstract

Background: Erythropoietin (Epo) exerts direct effects on white adipose tissue (WAT) in mice in addition to its erythropoietic effects, and in humans Epo increases resting energy expenditure and affect serum lipid levels, but direct effects of Epo in human WAT have not been documented. We therefore investigated the effects of acute and prolonged Epo exposure on human WAT in vivo. Method: Data were obtained from two clinical trials: 1) acute Epo exposure (rHuEpo, 400 IU/kg) followed by WAT biopsies after 1 h and 2) 10 weeks treatment with the erythropoiesis-stimulating agent (ESA) Darbepoietin-alpha. Biopsies were analyzed by PCR for Epo receptor (Epo-R) mRNA. A new and highly specific antibody (A82, Amgen) was used to evaluate the presence of Epo-R by western blot analysis in addition to Epo-R signaling proteins (Akt, STAT5, p70s6k, LYN, and p38MAPK), activation of lipolytic pathways (ATGL, HSL, CGI-58, G0S2, Perilipin, Cidea, Cidec, AMPK, and ACC), and mitochondrial biogenesis (VDAC, HSP90, PDH, and SDHA). Results: No evidence of in vivo activation of the Epo-R in WAT could be documented despite detectable levels of Epo-R mRNA.Conclusion: Thus, in contradiction to animal studies, Epo treatment within a physiological relevant range in humans does not exert direct effects in a subcutaneous WAT.

Diabetes mellitus induced by somatostatin analogue therapy is not permanent in acromegalic patients

“…Changes in the metabolic status occurred despite the biochemical control of acromegaly due to the SSA therapy. These data are in keeping with previous studies which reported that hyperglycaemia is a common side effect of SSAs.…”

Targeting either GH or IGF-I during somatostatin analogue treatment in patients with acromegaly: a randomized multicentre study

“…It remains to be tested if a more prolonged study period will translate into detectable changes in QoL or other non-biochemical endpoints. Our observations on insulin, FFA and glucose levels during the OGTT are in accordance with previous studies (11,12,13) and reflect the suppressive effects of SA on insulin secretion. It is also noteworthy that a positive correlation between insulin AUC during OGTT and IGF-I was recorded only in surgery patients, which indirectly supports a suppressive effect of SA on insulin-induced hepatic IGF-I.…”

“…IGF-I standard deviation scores (SDS) at the time of acromegaly diagnosis were calculated post hoc based on IGF-I data from each patient record using the corresponding age-related cut-off levels. Serum levels of insulin, glucose and FFA were measured as previously published (13).…”

Acromegaly and cardiovascular risk - In light of 30 cases

“…The various therapeutic means of acromegaly have a varied effect on carbohydrate metabolism: in most cases, the surgical treatment allows the concomitant cure of diabetes, the somatostatin analogues and pasireotide have a hyperglycemic effect, and the antagonists of the GH have a hypoglycemic effect [11][12][13][14][15][16][17].…”